Synthesis and nicotinic receptor activity of chemical space analogues of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU-282,987) and 1,4-diazabicyclo[3.2.2]nonane-4-carboxylic acid 4-bromophenyl ester (SSR180711).

The Chemical Universe Generated Databases up to 11 atoms of CNOF (GDB-11) and up to 13 atoms of CNOClS (GDB-13) were used to enumerate analogues of the diamine part of two known α7 nicotinic receptor agonists and construct libraries of virtual analogues of these drugs. The libraries were scored using structure-based (docking to the nicotine binding site of the acetylcholine binding protein 1uw6.pdb) or ligand-based (similarity to the parent drugs) methods, and the top-scoring virtual ligands were inspected for easily accessible synthetic targets.

Exploring α7-Nicotinic Receptor Ligand Diversity by Scaffold Enumeration from the Chemical Universe Database GDB.

Virtual analogues (1167860 compounds) of the nicotinic α7-receptor (α7 nAChR) ligands PNU-282,987 and SSR180711 were generated from the chemical universe database GDB-11 by extracting all aliphatic diamine analogues of the aminoquinuclidine and 1,4-diazabicyclo[3.2.2]nonane scaffolds of these ligands and converting them to the corresponding aryl amides using five different aromatic acyl groups.

Catalysis of 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives in enantioselective anti-Mannich-type reactions: importance of the 3-acid group on pyrrolidine for stereocontrol.

The development of enantioselective anti-selective Mannich-type reactions of aldehydes and ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives is reported in detail. Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently catalyzed the reactions of aldehydes with alpha-imino esters under mild conditions and afforded anti-Mannich products with high diastereo- and enantioselectivities (anti/syn up to 99:1, up to >99% ee). For the reactions of ketones with alpha-imino esters, (R)-3-pyrrolidinecarboxylic acid was an efficient catalyst (anti/syn up to >99:1, up to 99% ee).

Phosphine-dependent stereoselectivity in the mitsunobu cyclodehydration of 1,2-diols: stereodivergent approach to triaryl-substituted epoxides.

Triaryl-1,2-ethanediols, readily available from natural mandelic acid, can be stereospecifically converted into their corresponding chiral nonracemic epoxides by means of a Mitsunobu cyclodehydration reaction. Upon selection of the phosphine component in the reaction, the two enantiomers of the final epoxides are accessible in high enantiomeric excess. In view of this surprising phosphine-dependent stereoselectivity, here we examine the influence of the steric and electronic nature of both the phosphine and the substrate.

Synthesis of heavily substituted 1,2-amino alcohols in enantiomerically pure form.

[reaction: see text] A simple and convenient methodology for the preparation of optically pure 2-amino-2-aryl-1,1-diphenylethanols is presented. Allylamine was found to produce the ring-opening of triaryloxiranes in a regioselective and a stereospecific fashion. Removal of the allyl protecting group provided the free 1,2-amino alcohols in enantiomerically pure form.